This is an NIH Pathway to independence Award (K99/R00) grant proposal, intended to promote the career of Dr. Yoshihiro Komatsu, PhD, a research fellow at the University of Michigan, School of Dentistry, into an independent research position. The Candidate is a trained mouse developmental biologist with a significant track record of research in the fields of craniofacial development and early embryogenesis for addressing the etiology of birth defects and congenital diseases in human. His goal is to secure a tenure-track faculty position and establish his own research program in the field of craniofacial skeletal malformations and human ES cell- based cartilage/bone tissue regeneration. During the mentored (K99 phase in this award), the Candidate will attend advanced scientific workshops, career development sessions, ethics training and education in responsible conduct of research. He will work within a rich and collaborative environment of Craniofacial Developmental Biology at University of Michigan, School of Dentistry, under the mentorship of the Department Chair, Dr. Paul Krebsbach, DDS, PhD, and co-mentors Dr. Yuji Mishina, PhD and Dr. Vesa Kaartinen, PhD. During the K99 phase, the Candidate will study the role of BMP signaling through BMP type I receptor, ACVR1, to elucidate chondrogenic cell fate determination in neural crest cells during craniofacial development. Meanwhile, the Candidate will be trained in the experimental techniques for human ES cells and developing its rational research strategies. In addition, the candidate will increase his inventory of complementary analysis methods for craniofacial developmental studies. These achievements will be the fundamental bridge to an independent (R00) phase. During the independent (R00 phase of this award), the Candidate will elucidate the role of BMP signaling that regulates chondrocyte differentiation in neural crest-derived mesenchymal progenitors and human ES-derived mesenchymal stem cells (MSC). One of the proposed studies during R00 will focus on the regulation of chondrocyte differentiation by BMP signaling through ACVR1 in neural crest-derived mesenchymal progenitors during craniofacial development. We expect to discover novel mechanisms for how an excess amount of BMP signaling through ACVR1 leads to craniofacial skeletal malformation. Another project during R00 will focus on the molecular mechanisms of how BMP signaling through ACVR1 governs the chondrocyte differentiation in human ES-derived MSC. We anticipate uncovering novel information regarding BMP signaling and its practical role in effectively generating chondrocytes from human ES cells. This research has major health relevance, because craniofacial skeletal malformations are one of the most frequent disorders in human. In addition, this research directly connects the urgent health care that is needed to establish the strategies of generating chondrocytes using human ES cells since more than one million patients undergo facial cartilage reconstruction-related procedures every year, a costly treatment. PUBLIC HEALTH RELEVANCE: This proposed project is designed to elucidate the function of BMP signaling for chondrogenic cell fate determination in neural crest cells. Our study will yield novel and critical insights into the molecular pathogenesis of craniofacial skeletal abnormalities in humans, and will also provide novel techniques for the controlled differentiation of functional chondrocytes from human ES cells for tissue engineering applications.